Delivery of controlled-release system(s)

ABSTRACT

The present invention is a method and a dosage unit for delivery of a controlled-release system. The dosage unit is a quick dissolve unit which can be prepared by mixing uncured shearform matrix and a controlled-release system, either molding or compacting a unit dosage form and curing the shearform matrix. The controlled-release systems used in the present invention include instantaneous release components, delayed release components, sustained release components, and combinations thereof.

This is a divisional of application Ser. No. 08/334,729 filed on Nov. 4,1994 U.S. Pat. No. 5,567,439, which is a continuation-in-partapplication of U.S. application Ser. No. 08/259,496 abandoned, (Atty.Dkt. No. 447-105) and U.S. application Ser. No. 08/259,258 (Atty. Dkt.No. 447-106), both of which were filed Jun. 14, 1994. The contents ofboth patent applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to controlled release systems, and, inparticular to improved delivery of controlled release system or systems.

The convenience of administering a single dose of a medication whichreleases active ingredients in a controlled fashion over an extendedperiod of time, as opposed to the administration of a number of singledoses at regular intervals, has long been recognized in thepharmaceutical arts. The advantage to the patient and clinician inhaving consistent and uniform blood levels of medication over anextended period of time are likewise recognized. The advantages of avariety of controlled-release dosage forms are well known. Among themost important advantages are: (1) increased contact time for the drugto allow for local activity in the stomach, intestine or other locus ofactivity; (2) increased and more efficient absorption for drugs whichhave specific absorption sites; (3) the ability to reduce the number ofdosages per period of time; (4) employment of less total drug; (5)minimization or elimination of local and/or systemic side effects; (6)minimization of drug accumulation associated with chronic dosing; (7)improved efficiency and safety of treatment; (8) reduced fluctuation ofdrug level; and (9) better patient compliance with overall diseasemanagement.

Additionally, many experts believe controlled release drug delivery hasmany important non-therapeutic ramifications as well, including afinancial saving to the patient in terms of fewer lost work days,reduced hospitalization and fewer visits to the physician.

It is known that certain design parameters are critical to proper drugdelivery. Typically, they are: (1) delivering the drug to the targettissue; (2) supplying the drug in the correct temporal pattern for apredetermined period of time; and (3) fabricating a delivery system thatprovides drug in the desired spatial and temporal pattern. Controlledrelease drug delivery systems are intended to utilize these parametersto achieve the aforementioned advantages when compared to conventionalpharmaceutical dosing.

"Controlled-release" is used herein to describe a method and compositionfor making an active ingredient available to the biological system of ahost. Controlled-release includes the use of instantaneous release,delayed release, and sustained release. "Instantaneous release" isself-explanatory in that it refers to immediate release to the biosystemof the host. "Delayed release" means the active ingredient is not madeavailable to the host until some time delay after administration.(Dosages are usually administered by oral ingestion in the context ofthe present invention, although other forms of administration are notprecluded from the scope of the present invention). "Sustained Release"generally refers to release of active ingredient whereby the level ofactive ingredient available to the host is maintained at some level overa period of time. The method of effecting each type of release can bevaried. For example, the active-ingredient can be associated physicallyand/or chemically with a surfactant, a chelating agent, etc.Alternatively, the active ingredient can be masked by a coating, alaminate, etc. Regardless of the method of providing the desired releasepattern, the present invention contemplates delivery of acontrolled-release system which utilizes one or more of the "release"methods and compositions. Moreover, the present invention can be anelement of the release method and/or composition, especially withrespect to instantaneous release systems(s).

The patent and scientific literature is replete with various sustainedrelease (SR) methods and formulations. For common methods of obtainingSR systems, see Sustained and Controlled Release Drug Delivery Systems,Robinson, Joseph R., Ed., PP 138-171, 1978, Marcel Dekker, Inc. NewYork, N.Y. For example, it is known to fill polymeric capsules with asolid, liquid, suspension or gel containing a therapeutic agent which isslowly released by diffusion through the capsule walls. Heterogeneousmatrices, for example compressed tablets, control the release of theirtherapeutic agents either by diffusion, erosion of the matrix or acombination of both. Other SR systems focus on the fabrication oflaminates of polymeric material and therapeutic agent which are thenformed into a sandwich, relying on diffusion or erosion to controlrelease of the therapeutic agent. Liquid-Liquid encapsulated in aviscous syrup-like solution of polymer, have also been known to beuseful in controlling release of the therapeutic agent. Additionally, itis generally known that heterogeneous dispersions or solution oftherapeutic agents in water-swellable hydrogel matrices are useful incontrolling the release of the agent by slow surface-to-center swellingof the matrix and subsequent diffusion of the agent from thewater-swollen part of the matrix.

During dissolution of a controlled-release matrix tablet, the dosageform generally remains as a non-disintegrating, slowly eroding entityfrom which the therapeutic agent leaches out, through a diffusioncontrolled process. Conventional SR formulations are generally designedto release their actives over an extended period of time, usually 8-24hours. Conventional SR formulations use waxes or hydrophilic gums as theprimary drug carriers to prolong the release of the active ingredients.In conventional wax matrix tablet formulations, the drug is dispersed inthe wax matrix in the molten state. Conventional waxes and waxymaterials used in pharmaceutical formulations are carnauba wax,spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol,beeswax, partially hydrogenated vegetable oils, ceresin, paraffin,myristyl alcohol, stearyl alcohol, cetylalcohol and stearic acid. Theyare generally used in amounts of about 10 to about 50% by weight of thetotal formulation.

Hydrophilic gums have also been known to be reasonably effective as SRcarriers for both high-dose and low-dose drugs. Typical hydrophilic gumsused as SR carrier materials are acacia, gelatin, tragacanth, veegum,xanthan gum, carboxymethyl cellulose (CMC), hydroxypropl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and hydroxyethylcellulose (HEC). Generally these materials are present in amounts ofabout 10 to 50% by weight of the final formulation.

Starch USP (potato or corn) is commonly used as a component inconventional tablet or hard shell capsule formulations. It generallyfunctions in conventional applications as a diluent or as a disintegrantin oral dosage forms. Starch paste is also often used as a binder inthese products. Various modified starches, such as carboxymethyl starchcurrently marketed under the trade name Explotab or Primojel are usedboth in tablets and capsules as disintegrating agents. The literaturediscloses that native and modified starches are useful in promotingrapid release of drugs from solid oral dosage forms. Additionally,native starch has been used in some instances as a binder to producegranulations of active drug substances. More recently, pregelatinizedstarch has been reported as being useful as an SR matrix fortheophylline formulations by Herman and Remon, "Modified Starches asHydrophilic Matrices for Controlled Oral Deliver; III Evaluation ofSustained-Release Theophylline Formulations Based on Thermal ModifiedStarch Matrices in Dogs," in International Journal of Pharmaceutics,63(1990) 201-205. In sustained release applications several types ofmodified starch were mixed with anhydrous theophylline (60:40 W/W) aswell as with silicon dioxide (Aerosil 200) and sodium benzoate. In priorpapers, (International Journal of Pharmaceutics, volumes 56 (1988)145-153; 56 (1989) 51-63; and 56 (1989) 65-70) the authors discussed theuse of both drum-drying and extrusion of native starches to obtainpartial or full pregelatinization.

The existing sustained release technologies generally involve relativelycomplicated formulations and manufacturing processes which are difficultand expensive to precisely control. For example, one well known SRdelivery system, OROS, marketed by the Alza Corporation, involves laserdrilling through a tablet to create a passage for the release of thedrug from the tablet core.

In all controlled release technologies it is desirable to be able toincorporate the active ingredient in its controlled-release pattern in asingle dosage unit without deteriorating the active ingredient.Moreover, the dosage unit should be able to deliver the system withoutinterfering with its release pattern.

Various methods have been devised to enable controlled-release systemsto be delivered to a host without destruction of the delivery systemduring manufacturing, handling, and sales. For example,controlled-release systems have been provided in the form of beads orparticles which are packaged in a gelatin capsule for oral dosage. Thismethod of delivery of the controlled-release system prevents damage tothe coating on the beads.

In many cases it may be desirable to provide an oral dosage form as atablet. However, when controlled-release systems are incorporated in achewable tablet, chewing of the tablet may often rupture the coatings onthe active ingredient. This results in unpredictable release rates anddelivery to the biosysteri of the host. Moreover, whencontrolled-release components are incorporated in compression tablets,the extremely high pressure required to tablet can be expected torupture the coatings. Consequently, the compression tablet form ofdelivery is not usable, or extremely tough elastic coatings are requiredto withstand normal tablet pressures.

Furthermore, when controlled-release active ingredients are incorporatedin compression tablets, it may be difficult for many people to swallowsuch tablets. Furthermore, dissolution of high compression tablets isoften small and erratic, resulting in localized hot spots of alimentarytract irritation where disintegration and release of the activeingredient finally occurs.

The present invention overcomes the disadvantages of the prior art byoffering a simple and inexpensive means of incorporating acontrolled-release system in a unit dosage form which avoids theshortcomings normally associated with unit dosage delivery systems.

SUMMARY OF THE INVENTION

In a first embodiment of the present invention a method of preparing arapid or quick dissolve comestible unit is provided by mixing uncuredshearform matrix and a controlled-release system, molding the mixture toform a unit dosage form, and curing the shearform matrix. Preferably,the shearform matrix includes a crystallization enhancer and/or abinding aid.

As used herein, controlled-release system can include a componentselected from the group consisting of instantaneous release components,delayed release component(s), sustained release component(s), andcombination thereof. Instantaneous release components can be provided bysimply inclusion of raw active as an ingredient with the shearformmatrix or can include a dispersion enhancer such as a surfactant, etc. Adelayed release component is a component which has been treated bycoating or otherwise to provide delayed bio-availability in the host.Such systems include, but are not limited to, polymeric coatings,biodegradable coatings, etc. Sustained release components are componentswhich have been designed to provide a constant dosage release to thebiosystem over a period of time. The present invention also includescombinations thereof.

The shearform matrix used to form dosage units in accordance with theinvention can be made with flavors and/or sweeteners included in thefeedstock used to make the matrix. Flavors can be chosen from naturaland synthetic flavoring liquids. Sweeteners are those materials whichprovide sweetness to the matrix in addition to sweetness which isprovided by the carrier material used to form the matrix, e.g., sucrose.

The mixture can be molded by being introduced in a unit dosage well andtamping the mixture therein. The tamped mixture is then cured by beingsubjected to environmental conditions of heat, moisture, and pressurewhich induce crystallization. For example, the unit can be cured byincreasing the heat under substantially constant moisture condition. Theheat can be increased by subjecting the tamped unit to microwave energy.

Another type of additive which can be used in the present invention isan effervescent disintegration agent. The term effervescentdisintegration agent(s) includes compounds which evolve gas. Thepreferred effervescent agents evolve gas by means of chemical reactionswhich take place upon exposure of the effervescent disintegration agentto saliva in the mouth. The agent or agents can be included in severalways in the units of the present invention. First of all the agents canbe incorporated in the matrix by mixing with the feedstock prior toflash flow processing. Alternatively, the entire effervescent agent canbe mixed with the shearform matrix after it has been produced by flashflow techniques. As yet a third alternative, one part of the agent canbe included in the feedstock which is flash flow processed while theother part of the agent can be incorporated after flash flow processing.In any event, the effervescent disintegration agent provides forcontrolled and rapid disintegration of the tablet when placed in themouth and provides for a positive organoleptic sensation by theeffervescent action in the mouth. The texture, speed and sensation ofdisintegration can especially be adapted for use by children incombination with taking one or more of the medicaments contemplated foruse in the present invention.

"Tamping" is used herein to mean that the mixture is subjected tocompression pressure of less than about 500 lbs. per sq. in. (psi),preferably less than 250 psi, and most preferably from about 20 to about100 psi.

Another method of identifying the compression force required to molduncured matrix in accordance with the present invention is byidentifying the density resulting from tamping. The product of thepresent invention should be compressed in its uncured condition to adensity of not greater than about 1.2, preferably not greater than about0.8, and most preferably not greater than about 0.65. In one mostpreferred embodiment, the density of the finished product is between0.25 and 0.40.

The product prepared in accordance with the method set forth above candissolve in the mouth of the consumer in less than 10 seconds. Usually,well made product produced in accordance with this process will dissolvewithin less than 5 seconds, and, most preferably less than 3 seconds.The most highly dissoluble units have been described as literally"exploding" in the mouth.

In this first embodiment, the present invention also includes acomposition for delivering a controlled-release system wherein thecontrolled-release system is incorporated in a molded saccharide-basedcrystalline structure. The composition also includes thesaccharide-based structure which has a bi-dimensionally stabilizedcrystalline sugar. The sugar is produced by forming a sugar crystallineframe from an outer portion of an amorphous shearform sugar mass, andsubsequently converting the remaining portion of the mass to asubstantially completely crystalline structure. The product ispreferably monodispersed and is also preferably microcrystalline. Fordefinitions relating to monodispersed and microcrystalline as well asother definitions relating to the composition aspects of the presentinvention, reference is made to parent U.S. application Ser. No.08/133,669, filed Oct. 7, 1993, which is incorporated herein byreference. The shearform mass can also include an additive which isco-crystallized in a crystalline product. The amorphous shearform massis substantially rod-shaped, and has two dimensions lying in across-sectional plane of the rod. The single dimension extends along alinear axis of the rod. Preferably, the monodispersed structurallystabilized cross-section does not exceed 50 μm, and preferably does notexceed 15 μm.

Yet another manifestation of the first embodiment of the presentinvention is a method of administering an active ingredient to a humanhost. The method includes ingesting a quick dissolve comestible unitprepared by the method of the present invention, i.e., mixing uncuredshearform matrix and an active ingredient, followed by molding a unitdosage and curing the shearform matrix in the unit dosage form. The nextstep requires the host to retain the quick dissolve unit in the oralcavity for a time sufficient to contact the unit with water while in theoral cavity. Finally, the human host introduces water to the oral cavitywhile the unit is retained therein to enhance dissolution of the dosageunit.

As a result of the process of the first embodiment described herein, arapidly dissolving dosage unit can be manufactured on a continuous basisand even prepared for shipment to the consumer in a single manufacturingline. The product can be made to provide the stunning sensation ofexploding in the oral cavity upon ingestion by the consumer.

In a second embodiment of the present invention a method of preparing acomestible unit which quickly disperses in the mouth of the consumer isprovided. The method includes initiating crystallization of shearformmatrix either before or after combining the shearform matrix with adelivery system, as defined hereinabove, to form flowable, compactiblemicro-particulates. The combination, which includes at least partiallycrystallized shearform matrix, is then compacted to form the comestibleunit.

Preferably, a crystallization/binding promoter is used to enhance theformation of flowable, compactible micro-particulates. Thecrystallization/binding promoter can be selected from the groupconsisting of an alcohol, such as ethanol, polyvinylpyrrolidone and acombination thereof. The promoter can also be a surface active agent.Surface active agents can be added to feedstock used to form the matrix.Alternatively, polydextrose can be used as a promoter by inclusion inthe feedstock.

The shearform matrix can be prepared by flash flow processing feedstockwhich includes saccharide based material as a carrier component. Sucroseis a preferred carrier, and it can be combined with other saccharidebased carrier components, such as dextrose, and sugar alcohols, such assorbitol, mannitol, etc. The feedstock can also include acrystallization enhancer such as a surfactant, e.g., tweens, spans, etc.

In order to form the comestible unit, a medium compression force can beused without fear of disrupting the disintegratability of the unit. Thecompression force need not exceed ten (10) Strong Cobb Units ("SCU"),and preferably does not exceed medium compression forces of between six(6) and eight (8) SCU's. In some embodiments, a low compression forcecan also be used. In either event, tablets produced according to theinvention can be made low density and easily disintegrated.

Another method of identifying the compression force required to molduncured matrix in accordance with the present invention is byidentifying the density resulting from compacting. The product of thepresent invention should be compacted to a density of not greater thanabout 1.2, and preferably not greater than about 0.8.

It has been found that the components of the delivery system are not"tied-up" with the components of the dosage unit. Consequently, activeingredients pharmaceuticals are made available to bio-systems for whichthey have been administered.

Another type of additive which can be used in the present invention isan effervescent disintegration agent. The term effervescentdisintegration agent(s) includes compounds which evolve gas. Thepreferred effervescent agents evolve gas by means of chemical reactionswhich take place upon exposure of the effervescent disintegration agentto saliva in the mouth. The agent or agents can be included in severalways in the units of the present invention. First of all, the agents canbe incorporated in the matrix by mixing with the feedstock prior toflash flow processing. Alternatively, the entire effervescent agent canbe mixed with the shearform matrix after it has been produced by flashflow techniques. As yet a third possibility, one part of the agent canbe included in the feedstock which is flash flow processed while theother part of the agent can be incorporated after flash flow processing.In any event, the effervescent disintegration agent provides forcontrolled and rapid disintegration of the tablet when placed in themouth and provides for a positive organoleptic sensation by theeffervescent action in the mouth. The texture, speed and sensation ofdisintegration can especially be adapted for use by children incombination with taking one or more of the medicaments contemplated foruse in the present invention.

The present invention also includes a composition for delivering acontrolled-release delivery system wherein the active ingredient isincorporated in a molded saccharide-based crystalline structure. Thecomposition also includes the saccharide-based structure which has abi-dimensionally stabilized crystalline sugar as defined hereinbefore.

Yet another manifestation of this embodiment is a method ofadministering an active ingredient to a human host. The method includesingesting a quick dissolve comestible unit prepared by the method of thepresent invention. The next step requires the host to retain the quickdissolve unit in the oral cavity for a time sufficient to contact theunit with water while in the oral cavity. Finally, the human hostintroduces water to the oral cavity, while the unit is retained therein,to enhance dissolution of the dosage unit.

In all embodiments of the present invention, another feature includesreinforcing particles which inhibit destruction of components of thecontrolled-release system. Reinforcing particles have a size, shape, andhardness which are intended to withstand destructive pressure of aninadvertant bite by the consumer. For example, reinforcing particles canhave a size which is up to 100 times larger that controlled-releasecomponents. The hardness is preferable greater than the hardness of thecomponents of the controlled-release system. The shape is preferably onewhich does not detract from the texture and mouthfeel of the dosage unitduring ingestion.

As a result of the present invention, a rapidly dispersible comestibleunit can be manufactured for shipment and sales to consumers. The methodof the present invention is such that the manufacturing can proceed on acontinuous commercial scale. A unit can be formed which is durable andcan withstand handling associated with packaging and distribution.

Moreover, the dispersability of the unit is perceived as nearlyinstantaneous. Consequently, the consumer does not experiencedisagreeable effects of unpleasant ingredients lingering in the oralcavity.

Furthermore, the component(s) of the controlled-release system can bemade available to the host virtually without interference withingredients therein.

These and other advantages of the present invention will be appreciatedfrom the detailed description and examples which are set forth herein.The detailed description and the examples enhance the understanding ofthe invention, but are not intended to limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a method of making comestible units whichdisintegrate quickly in the mouth of the consumer. The units produced inaccordance with the present invention disintegrate nearlyinstantaneously. However, these units or tablets are capable of beingmanufactured so that they can be handled for packaging and distributionwithout deterioration of the integrity of the comestible units.

In the past, comestible units such as tablets have been made primarilyby compressing feedstock under extremely high-pressure in order toprovide the necessary hardness for handling required during packagingand distribution. Consequently, prior art tablets so produced arelimited in that their high density reduces the capability of making themquickly disintegratable in the mouth. High density packing resultingfrom the high compression hinders the disintegration and wetting of theinterior portion of the tablet. This aspect of the prior art has beenimproved by the technology disclosed in parent U.S. application Ser. No.194,682, filed on Feb. 10, 1994.

As a result of the present invention, however, a significant stepforward has been made in the art of preparing comestible units whichdisintegrate very quickly in the mouth and which can deliver acontrolled-release system. In fact, tablets produced by the presentinvention disintegrate within seconds. The product is prepared by aunique combination of processing steps. The present invention alsoincludes products which are produced by the new process.

The first step of the procedure of the first embodiment is to mix anuncured shearform matrix and a controlled-release system which includesan active ingredient, to prepare for molding a unit dosage. "Shearformmatrix" in the present invention means a matrix produced by subjecting afeedstock which contains a carrier material to flash flow processing.

Flash flow processing can be accomplished several ways. Flash-heat andflash-shear are two processes which can be used. In the flash-heatprocess the feedstock material is heated sufficiently to create aninternal flow condition which permits part of the feedstock to move atsubparticle level with respect to the rest of the mass and exit openingsprovided in the perimeter of a spinning head. The centrifugal forcecreated in the spinning head flings the flowing feedstock materialoutwardly from the head so that it reforms with a changed structure. Theforce necessary to separate and discharge flowable feedstock iscentrifugal force which is produced by the spinning head.

One preferred apparatus for implementing a flash heat process is a"cotton candy" fabricating type of machine. The spinning machine used toachieve a flash-heat condition is a cotton candy machine such as theEcono-Floss Model 3017 manufactured by Gold Medal Products Company ofCincinnati, Ohio. Any other apparatus or physical process which providessimilar forces and temperature gradient conditions can also be used.

In the flash-shear process, a shearform matrix is formed by raising thetemperature in the feedstock material which includes a non-solubilizedcarrier, such as a saccharide-based material until the carrier undergoesinternal flow upon application of a fluid shear force. The feedstock isadvanced and ejected while in internal flow condition, and subjected todisruptive fluid shear force to form multiple parts or masses which havea morphology different from that of the original feedstock.

The multiple masses are cooled substantially immediately after contactwith the fluid shear force and are permitted to continue in a free-flowcondition until solidified.

The flash shear process can be carried out in an apparatus which hasmeans for increasing the temperature of a non-solubilized feedstock andmeans for simultaneously advancing it for ejection. A multiple heatingzone twin screw extruder can be used for increasing the temperature ofthe non-solubilized feedstock. A second element of the apparatus is anejector which provides the feedstock in a condition for shearing. Theejector is in fluid communication with the means for increasing thetemperature and is arranged at a point to receive the feedstock while itis in internal flow condition. The ejector is preferably a nozzle whichprovides high pressure ejection of the feedstock material. Seeco-pending commonly-owned U.S. patent application Ser. No. 965,804 filedOct. 23, 1992 entitled "Process For Making Shearform Matrix," which isincorporated herein by reference.

The feedstock for producing shearform matrix includes a carriermaterial. The carrier material can be selected from material which iscapable of undergoing both physical and/or chemical changes associatedwith flash-flow processing. Materials useful as matrices may be chosenfrom those carbohydrates which are capable of forming free-formagglomerates upon being processed.

Preferred materials useful as matrices may be chosen from such classesas "sugars". "Sugars" are those substances which are based on simplecrystalline mono- and di-saccharide structures, i.e., based on C₅ and C₆sugar structures. "Sugars" include sucrose, fructose, lactose, maltose,and sugar alcohols such as sorbitol, mannitol, maltitol, etc. Thepreferred choice of sugar in the present invention is sucrose.

Preferred combinations of sugars includes sugars as used herein incombination with other mono-, di-, tri-, and polysaccharides up to 50%of the total amount, preferably up to 30% and most preferably up to 20%.

A shearform product is used in the technique of the present invention toobtain the new sugar product. A shearform sugar product is asubstantially amorphous sugar which results from subjecting sugar toheat and shear sufficient to transform crystalline (usually granulated)sugar to amorphous sugar without the use of a solution. Thus, in thesense of the present invention, a shearform sugar product ischaracterized as a sugar product resulting from a non-solubilized sugar.It is the starting material for forming the unique crystalline productof the present invention.

Other carrier materials can be used, but preferably in combination withsugar - - - not as a total replacement.

Maltodextrins are an example of other carrier materials. Maltodextrinsinclude those mixtures of carbohydrates resulting from hydrolysis of asaccharide feedstock which are described as solids having a DE of up toand including 65.

The feedstock can also include maltooligo-saccharides produced byselective hydrolysis of cornstarch followed by removal of high and lowmolecular weight compounds. The general description ofmalto-oligosaccharides as contemplated herein is set forth in co-pendingU.S. application Ser. No. 07/847,595 filed Mar. 5, 1992.

Polydextrose is also contemplated for use as a carrier. Polydextrose isa non-sucrose, essentially non-nutritive carbohydrate substitute. It canbe prepared through polymerization of glucose in the presence ofpolycarboxylic acid catalyst and polyols. Generally, polydextrose isknown to be commercially available in three forms: polydextrose A andpolydextrose K, which are powdered solids, and polydextrose N suppliedas a 70% solution. Each of these products also contain some lowmolecular weight components, such as glucose, sorbitol and certainoligomers. Regarding polydextrose, Applicants incorporate herein thecontents of co-pending, U.S. application Ser. No. 07/881,612 filed May12, 1992.

As previously mentioned, each of the carriers are used primarily incombination with sugars, and not as a total replacement.

Other materials which can be incorporated into the feedstock to enhancethe shearform matrix include flavors and sweeteners (other than thecarrier itself).

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationthereof. A non-limiting representative list of examples includes citrusoils such as lemon, orange, grape, lime and grapefruit and fruitessences including apple, pear, peach, grape, strawberry, raspberry,cherry, plum, pineapple, apricot or other fruit flavors.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral, i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime) decanal (orange, lemon), aldehydeC-8 (citrus fruits), aldehyde C-9 (citrus fruits), adlehyde C-12 (citrusfruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (greenfruit), and 2-dodecenal (citrus, mandarin), mixtures thereof and thelike.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof (when not used as a carrier); saccharin and its various saltssuch as the sodium salt; dipeptide sweeteners such as aspartame;dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside);chloro derivatives of sucrose such as sucralose; sugar alcohols such assorbitol, mannitol, xylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof. Other sweeteners may also be used.

Other ingredients can also be used in the present invention eitherduring the mixing stage, during the agglomeration stage, or after theagglomeration stage. Such ingredients are ingredients which are usefulin tabletting such as glidants which adhere to cohesive material andenhance flow properties. Flow property is enhanced by reducinginterparticle friction which otherwise exists. Glidants which can beused includes starch, talc, magnesium and calcium stearate, zincstearate, dibasic calcium phosphate, magnesium carbonate, magnesiumoxide, calcium silicate, and silica arogels.

Also color additives can be used in preparing tablets. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Yet a further embodiment of the present invention includes the use of aneffervescent disintegration agent. Its action can aid in the masking ofobjectionable taste of active ingredients such as vitamins, medicinesand/or minerals, etc. It is generally believed that the positiveorganoleptic sensation achieved by the effervescent action in the mouth,the texture, speed and sensation of disintegration aids in maskingundesirable flavor notes in the mouth.

In preferred embodiments of the present invention, the effervescentdisintegration agent may include at least one acid selected from thegroup consisting of citric acid, tartaric acid, malic acid, fumaricacid, adipic acid, succinic acid, acid anhydrides and acid salts andmixtures thereof, and at least one base selected from the groupconsisting of carbonate salts, bicarbonate salts and mixtures thereof.

The term effervescent refers to those agents which evolve gas, and thebubble or gas generating the action is most often the result of thereaction of a soluble acid source and an alkali metal carbonate orcarbonate source. The reaction of these two general classes of compoundsproduces carbon dioxide gas upon contact with water included in saliva.Carbonate sources include dry solid carbonate and bicarbonate salts suchas sodium bicarbonate, sodium carbonate, potassium bicarbonate andpotassium carbonate, magnesium carbonate and sodium sesequicarbonate,sodium glycine carbonate, L-lysine carbonate, arginine carbonate andamorphous calcium carbonate. While the food acids can be those indicatedabove, acid anhydrides of the above-described acids may also be used.Acid salts may include sodium, dihydrogen phosphate, disodium dihydrogenpyrophosphate, acid citrate salts and sodium acid sulfite. Other sourceof effervescence can be included and the present invention is notlimited to those specifically set forth herein.

Also as previously mentioned, the ingredients of the effervescent agentcan be included in one of at least three different ways. The firstmethod includes incorporating the entire effervescent agent in thefeedstock which is used to form the shearform product. The second mannerof incorporating an effervescent disintegrating agent is to include theentire agent as an additive which is mixed with shearform matrix afterit is formed. The third method contemplates incorporating one portion ofthe disintegrating agent in the shearform matrix and another portion ofthe disintegrating agent as an additive after formation of the shearformmatrix material. The artisan will determine the best way to preserve theagent for its disintegrative and effervescent properties upon ingestionby the host.

The shearform matrix used in the inventive process must be uncuredbefore it is molded. "Uncured" means amorphous or having a degree ofamorphousness which enables the formation of a dosage unit upon curing."Curing" means transforming the matrix from amorphous to crystallinewhile being sufficiently bound to produce a stable structure.

Curing can be enhanced by crystallization modifiers. Crystallizationmodifiers can be added to the feedstock before flash flow processing,such modifiers include, but are not limited to, surfactants (Spans™ andTweens™), dextrose, polyethylene glycol (PEG), polypropylene glycol(PPG), etc. These modifiers generally provide controlled acceleration ofcrystallization while the matrix is bound.

Crystallization modifiers enhance the formation of a crystalline frameand the conversion of the remaining mass. Enhancement as used withrespect to the process of the present invention principally meansacceleration of the process. Enhancement also includes contribution tothe strength of the crystalline structure, and predictability ofresults. Other benefits such as reduced-size product also is achieved byuse of crystallization modifiers.

Crystallization modifiers, which are preferably added to sugars beforebeing processed to amorphous shearform mass (or can be coated on thesugar), are used to affect the rate of crystallization. Water itself isa crystallization modifier, and is preferably included in the amorphousshearform sugar mass in an amount of between about 0.5% to about 2.0%.Non-saccharide hydrophilic organic materials (NSHMs) are also used ascrystallization modifiers. Even though some NSHMs are surfactants, othermaterials can be used. Materials found to be most effective have ahydrophilic to lipid balance (HLB) of 6 or greater, i.e., they have thesame degree of hydrophilicity as surfactants characterized by degree ofHLB. Such materials include, but are not limited to anionic, cationic,zwitterionic surfactants as well as neutral materials which have an HLBof six (6) or greater. Preferred NSHMs are hydrophilic materials havingpolyethylene oxide linkages. Also, the preferred NSHM's have a molecularweight of at least 200 and preferably at least 400.

Lecithin is one surface active agent for use in the present invention.Lecithin can be included in the feedstock in an amount of from about0.25 to about 2.00% by weight. Other surface active agents include, butare not limited to, the Spans™ and Tweens™ which are commerciallyavailable from ICI Americas Inc. Carbowax™ is yet anothercrystallization modifier which is very useful in the present invention.Preferably, Tweens™ or combinations of surface active agents are used toachieve the desired HLB.

By use of a surfactant the process and product of the present inventioncan be reproduced with a high degree of predictability. As additionalcrystallization modifiers which enhance the procedure and product of thepresent invention are identified, Applicants intend to include all suchadditional crystallization modifiers within the scope of the inventionclaimed herein.

The process of the present invention requires mixing an additive withthe uncured shearform matrix. When the shearform matrix is in the formof a floss, it is preferably chopped first to reduce the volume of theproduct without compressing it. The additive can be any ingredient oringredients needed to supply the dosage unit with the requiredcharacteristics. The primary ingredients are medicinal substances.

In a second embodiment of the present invention, the controlled-deliverysystem is combined before or after initiating crystallization.

"Initiating crystallization" in the present invention means to inducecrystallization. Shearform matrix used in the present invention containsa substantial amount of amorphous sugar. Crystallization can beinitiated several ways. For example, crystallization promoters can beincluded in the feedstock used to make the shearform matrix.Crystallization promoters include surface active agents such as Tweens™,Spans™, and polydextrose, and mixtures thereof. Crystallization can alsobe initiated by adding a crystallization agent to the matrix before orafter combining with an additive. Therefore, initiating crystallizationin the present invention can occur before or after combining with theadditive.

"Combining" an additive with shearform matrix to form flowable,compactible micro-particulates means to add and mix an additive beforeor after initiating crystallization to form a medium which consists ofmicro-particulates. Micro-particulates are discreet entities whichappear to "roll" readily or "flow" in response to force of gravityand/or agitation. On a macroscopic scale micro-particulates appear as aflowable mass or medium. Consequently, the medium can be easily used intabletting machinery without clogging and/or creation of undue dust inthe ambient atmosphere.

The shearform matrix of the present invention is retrieved fromprocessing, and generally "chopped" before combining with the additive.The additive can be any ingredient or ingredients needed to supply thecomestible unit with the required characteristics. Preferably, theprimary ingredient of the additive is one or more medicinal substances.

Medicinal substances which can be used in the present invention arevaried. The medicinal substances can be encapsulated for controlledrelease. A non-limiting list of medicinal substances is as follows:antitussives, antihistamines, decongestants, alkaloids, mineralsupplements, laxatives, vitamins, antacids, ion exchange resins,anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics,analgesics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, anti-infectives,psycho-tropics, antimanics, stimulants, gastrointestinal agents,sedatives, antidiarrheal preparations, anti-anginal drugs,vasodialators, anti-hypertensive drugs, vasoconstrictors, migrainetreatments, antibiotics, tranquilizers, anti-psychotics, antitumordrugs, anticoagulants, antithrombotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypoglycemic agents, thyroid and antithyroid preparations, diuretics,antispasmodics, uterine relaxants, mineral and nutritional additives,antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics,cough suppressants, mucolytics, anti-uricemic drugs and mixturesthereof.

Especially preferred active ingredients contemplated for use in thepresent invention are antacids, H₂ -antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂ -antagonists.

Analgesics include aspirin, acetaminophen, and acetaminophen pluscaffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include antadiarrheals such as immodium AD,antihistamines, antitussives, decongestants, vitamins, and breathfresheners. Also contemplated for use herein are anxiolytics such asXanax; antipsychotics such as clozaril and Haldol; non-steroidalanti-inflammatories (NSAID's) such as Voltaren and Lodine;antihistamines such as Seldane, Hismanal, Relafen, and Tavist;antiemetics such as Kytril and Cesamet; bronchodilators such asBentolin, Proventil; antidepressants such as Prozac, Zoloft, and Paxil;antimigraines such as Imigran, ACE-inhibitors such as Vasotec, Capotenand Zestril; Anti-Alzheimers agents, such as Nicergoline; and Ca^(H)-Antagonists such as Procardia, Adalat, and Calan.

The popular H₂ -antagonists which are contemplated for use in thepresent invention include cimetidine, ranitidine hydrochloride,famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidineand aceroxatidine.

Other ingredients which may be included are fragrances, dyes, sweetenersboth artificial and natural, and other additives.

For example, fillers may be used to increase the bulk of the tablet.Some of the commonly used fillers are calcium sulfate, both di- and tribasic, starch, calcium carbonate, microcrystalline cellulose, modifiedstarches, lactose, sucrose, mannitol, and sorbitol.

Other ingredients includes binders which contributes to the ease offormation and general quality of the tablet. Binders include starches,pregelatinize starches, gelatin, polyvinylpyrrolidone, methylcellulose,sodium carboxymethylcellulose, ethylcellulose, polyacrylamides,polyvinyloxoazolidone, and polyvinylalcohols.

Lubricants can also be used to aid in tamping and compacting. Lubricantscan include, but are not limited to, the following: magnesium stearate,calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex,polyoxyethylene, monostearate, talc, polyethyleneglycol, sodiumbenzoate, sodium lauryl sulfate, magnesium lauryl sulfate and lightmineral oil.

Furthermore, disintegrants can be used to enhance the dispersibility ofthe compressed tablet in an aqueous environment. The dispersants caninclude starch, alginic acid, guar gum, kaolin, bentonite, purified woodcellulose, sodium starch glycolate, isoamorphous silicate, andmicrocrystalline cellulose. In view of the highly dissoluble nature ofthe product of the present invention, there is little need fordisintegrants.

Another ingredient useful in tabletting are glidants which adhere to thecohesive material in order to enhance flow properties by reducinginterparticle friction. Glidants which can be used include starch, talc,magnesium and calcium stearate, zinc stearate, dibasic calciumphosphate, magnesium carbonate, magnesium oxide, calcium silicate, andsilica aerogels.

Furthermore, dispersion enhancers can be used to enhance thebreakability of the compressed tablet in an aqueous environment. Thedispersants can include starch, alginic acid, polyvinylpyrrolidones,guar gum, kaolin, bentonite, purified wood cellulose, sodium starchglycolate, isoamorphous silicate, and microcrystalline cellulose as highHLB emulsifier surfactants. In view of the ease with which the productof the present invention disintegrates, there is little need fordisintegrants.

Color additives useful in preparing tablets include food, drug andcosmetics (FD&C) colors, drug and cosmetic (D&C) colors, or externaldrug and cosmetic (Ext. D&C) colors. These colors are dyes, theircorresponding lakes, and certain natural and derived colorants. Lakesare dyes absorbed on aluminum hydroxide.

In a preferred embodiment, the present invention is particularly usefulin preparing antacid tablets. Antacids are conveniently provided inchewable tablet form to provide a convenient method of deliveringantacid to the consumer. The chewable form provides an advantage in thatthe tablet is broken up into granules during chewing and mixed withsaliva before swallowing. This renders the tablet antacid formulation asuspension. One of the disadvantages of prior art antacid tablets isthat the mass of ingredients residing in the mouth during and afterchewing have objectional texture and taste. The present inventionovercomes these disadvantages because the ingredients virtually explodeinto dissolution. The texture is also significantly enhanced and theresidence time is substantially reduced.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate,calcium phosphate, citrate ion (acid or salt), amino acetic acid,hydrate magnesium aluminate sulfate, magaldrate, magnesiumaluminosilicate, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, magnesium oxide, magnesium trisilicate, milksolids, aluminum mono-ordibasic calcium phosphate, tricalcium phosphate,potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesiumaluminosilicates, tartaric acids and salts.

After the controlled-release system has been mixed with the uncuredshearform matrix, the result of mixture must be "molded" as a unitdosage form.

"Molding" is used herein to mean associating uncured (i.e.,uncrystallized) shearform matrix material closely enough to providebridging between crystallized matrix material upon curing. Generally,this requires force sufficient to provide intimate contact of fibersprior to curing, followed by crystallizing to form a bound continuouscrystalline structure throughout the tablet. Unlike conventionaltabletting which relies primarily on compression to provide thestructure, the present process utilizes the curing process to aid informing the end product. Consequently, mild compression forces can beused to mold the product. In a preferred embodiment, the compressionrequired to mold uncured matrix material is referred to as "tamping."

"Tamping" means compressing with force less than that required incompression tabletting, which is generally regarding as being on theorder of thousands of pounds per square inch (psi). The maximum pressureused in the present invention is only 500 psi, but in most cases willnever exceed about 250 psi, and, in the most preferred embodiments, notmore than 80 psi (e.g., 40 psi to 80 psi). These lower pressures arecalled tamping.

Another method of measuring the compression force required to "mold"uncured matrix is by product density. The product of the presentinvention should be compressed in an uncured condition to a density ofnot greater than about 1.20, preferably not greater than 0.8, and, mostpreferably, not greater than 0.65.

Inasmuch as one method the present invention requires extremely lowpressures for molding, it is possible to mold directly in plasticproduct wells which can be used as packaging for sales. Consequently,the present invention includes the concept of molding uncured matrixmaterials clearly in product wells such as plastic blister packagedepressions.

In the second embodiment, the present inventor requires compacting thecombination resulting from "combining" the controllable release deliverysystem and the shearform matrix.

"Compacting" in the present invention means to press into a comestibleunit, e.g., a tablet, at a pressure generally greater than about 500psi, but not necessarily as great as normal tabletting pressure, whichare on the order of magnitude of thousands of psi (i.e., at least about1000 psi). In one preferred embodiment wherein polydextrose (especially,Poly Dex™ brand polydextrose provided by A. E. Stanley & Co.) has beenincluded as a crystallization promoter, compaction pressure as low as 50psi has been found to be effective. In all cases herein, themicro-particulate medium being compacted includes shearform matrix whichhas been at least partially crystallized.

The combination of shearform matrix and the additive must be provided asflavorable, compactible micro-particulates. The micro-particulates areagglomerates of a sort which include the ingredients of the mixture, butwhich are relatively low density. The "micro-particulates" of thepresent invention are capable of withstanding relatively high compactionforce without experiencing an increase in density. Themicro-particulates can then be compacted under relatively highcompaction force to form a low density dosage unit having highstructural integrity, strength and excellent appearance.

Micro-particulates are preferably formed by combining the mixture with acrystallization/binding promoter such as ethanol (preferably 200 proof),polyvinylpyrrolidone, a combination thereof, as well as other agentswhich enhance the formation of micro-particulates without increasing thedensity of the mixture.

The micro-particulates resulting from the above step can then becompacted, e.g., 6-8 SCUs (Strong Cobb Units), whereby a structurallystrong tablet can be formed which has excellent appearance and can behandled without deterioration of the surface or structure.

After preparing shearform matrix and molding the uncured matrix, theproduct must be cured. Curing means binding and crystallizing the matrixmaterial substantially simultaneously. Curing is performed by subjectingproduct to heat and moisture sufficient to provide controlledcrystallization. Controlled crystallization occurs when points ofcontact of uncured matrix material become points of crystalline growthand crystallization of the material proceeds to provide crystallinestructures. Binding occurs at the points of contact, and thesimultaneous crystalline growth is such as to maintain structuralintegrity.

The "curing" process of the present invention involves a transformationfrom amorphous to crystalline state. The transformation must take placewhile the amorphous shearform matrix remains bound together.

Moreover, curing requires the transformation to take place withoutcollapsing the structural integrity of the matrix in its "formed"condition. Since amorphous shearform product is hygroscopic, thistransformation can be difficult. When points of contact between piecesof matrix can be made points of crystalline growth during curing,structural integrity is established and maintained. One way of promotingthe occurrence of this phenomenon is to include crystallizationenhancers, e.g., surfactants, any alcohol, polyethylene glycol,polypropylene glycol, etc. Without being bound by theory, it is believedcontrol of the propagation of crystalline growth as outlined above isimproved significantly by use of crystallization enhancers.

Prior to curing, the mixture of shearform matrix and active aremaintained at temperature and humidity below the glass transitiontemperature of the shearform matrix material.

Conditions suitable for curing can include ambient conditions of heatand moisture or modified ambient conditions. For example, it has beenfound that curing can be conducted at a temperature of 0°-90° C. at arelative humidity of 25-90%. In one case, it has been found that curingwill take place within 15 minutes at 40° C. and 85% r.h. In other cases,optimum temperature range has ben found to be at 20°-50° C. Microwaveenergy can be used to controlledly accelerate curing.

Generally, the crystallization is effected in an environment wherein thetabletted material cures to a water content of less than 5% by weight,and preferably less than 1% by weight based on the weight of the tablet.Thus, the curing environment, e.g., chamber or room, is maintained at arelative humidity which permits water pickup no greater than 5%, andpreferably less than 1%.

It has been found that curing product in a package well results inshrinkage of the tablet from the walls of the well. This feature isparticularly advantageous for purposes of manufacturing individualdosage units since molding and curing can be performed in the packageused for commercial sales. Consequently, several transfer steps can beeliminated.

Products prepared in accordance with the present invention have beenfound to have densities of from about 0.20 gm/cc² to about 0.90 gm/cc²,and some preferred embodiments have densities of from about 0.40 gm/cc²to about 0.65 gm/cc².

Another ingredient which can be included in the shearform matrix is abinding aid or agent. A binding agent is used to assist in the moldingstep and, in some cases, contributes to the dissolution capabilities ofthe finished product. Binding agents useful herein includelow-glass-transition materials. Some agents found useful include, butare not limited to, sorbitol, mannitol, lactose, etc. The binding agentsare flash flow processed with the carrier. Binding agents also aid inholding the matrix material in place for curing. In some cases portionsof the binder becomes part of the matrix material.

In the second embodiment of the present invention, one method ofmeasuring the results of the present invention is the ability to make alow density product. The micro-particulates are capable of beingsubjected to high-pressure without reducing the density of the resultingproduct. Accordingly, the product prepared in accordance with thepresent invention even after high-pressure-compaction will still remainbelow 1.2 grams per cubic centimeter (gr./cc), and preferably below 0.8gr./cc.

The pressure required to prepare tablets in accordance with the presentinvention exceed those generally required in the first embodimentdescribed herein, but are less than those previously required withnormal tabletting procedures (albeit some embodiments require no greatercompaction pressure than that set forth in U.S. application Ser. No.08/259,258). As a result of the increase pressure which can be used toform tablets in accordance with the present invention, the strength ofthe product is increased, and the hardness of the surface is alsoincreased. This results in a confection dosage unit which is able to behandled manually and machine processed without degradation of thesurface or structural integrity.

Micro-particulates retain their individual integrity and lines ofdisintegration are provided throughout the resulting unit. Moreover,since the mass can be subjected to relatively high-pressure-compaction,the surface of the resulting dosage unit is smooth, and the strength ofthe tablet is relatively high. Therefore, the resulting units can beeasily handled without deterioration of the surface appearance ordestruction of the comestible units.

In the formation of the micro-particulates the material preferablycontains up to 5% water, and most preferably up to 1% water. The watercan be provided by water contained in the ingredients such as thatcarried in the sugars or binders. Water can also be provided in smallamounts in the alcohol, such as in 200 proof alcohol which absorbsmoisture rapidly and generally contains small amounts of moisture, e.g.,up to 1% by weight. The additional moisture can be provided by ambientsurroundings such as the humidity in the air.

The present invention has been found to be well suited for preparationof antacid tablets and tablets in which antacids are used as aningredient to ameliorate the acid conditions in the body in order toassist drugs which do not tolerate acidic conditions. In the case ofantacids themselves, the instantaneous dispersion of the tablet in themouth prevents the residual chalky taste of a conventional antacidtablet. In the case of ingredients which do not tolerate acidicconditions, it is desirable to include the antacids plus the"acid-sensitive" pharmaceutical in a dosage unit prepared according tothe invention. For example, didanosine is an antiviral agent which doesnot tolerate an acidic environment well. Consequently, the use ofdidanosine in combination with an antacid such as calcium carbonate inthe same drug delivery system is an ideal method of introducing the drugto the body. The present invention includes the combination of an"acid-sensitive" ingredient and an antacid in a dosage unit.

The shearform matrix material used in the following examples is anamorphous sugar. Amorphous sugar as used herein means a sugar stockwhich contains a high percentage of amorphism, i.e., greater than 50% byweight, and preferably greater than 70% by weight of the sugar stock isamorphous.

EXAMPLE

A controlled release system was prepared in accordance with the presentinvention by preparing a shearform matrix using a combination of 49.75%sucrose, 0.025% Tween 80 as a surfactant, 40% Cantab™ (a crystallineform of a high D.E., Dextrose Equivalent, Corn Syrup product of PenwestFoods Co., Cedar Rapids, Iowa), and 10% D-Xylose. The shearform matrixwas collected and comminuted to a small consistent size and stored in anairtight container and subsequently formulated for tabletting.

The tablet formulation was prepared with 60% floss as set forth above,37% Contact brand cold medicine, 0.55% Aspartame, 0.5% coloring, 1%Comprital HD5 (a Glycerol Polyethylene Glycol Behenate product ofGattefosse Westwood, N.J.), and 0.50% Syloid 244 FP flow agent. Thecombination was blended in a manner which ensured the drug wassubstantially homogenously mixed with the other ingredients.

The combination was subsequently weighed into 0.7 gram samples andloaded into a press and tabletted by tamping at a 40 pound per squareinch pressure for approximately five seconds.

The resulting tablets had a very uniform and attractive surface, andmaintained good physical integrity. The tablets were sealed in a blisterpack. Tablets crystallized in the packaging over a 24 hour period.

The tablets produced by the process set forth above were rapidlydispersable in the oral cavity. The drug was also rapidly dispersed andit is believed that the process could be easily adapted to existingcommercial drug tabletting facilities.

Thus, while there had been described what are presently believed to bethe preferred embodiments of the present invention, other and furthermodification and changes can be made thereto without departing from thetrue spirit of the invention. It is intended to include all further andother modifications and changes which come within the true scope of theinvention as set forth in the claims.

What is claimed is:
 1. A composition for preparing uncured comestibleunits having controlled release properties comprising microparticulatescontaining a mixture of:a controlled-release system containing an activeingredient and amorphous saccharide-based shearform masses.
 2. Thecomposition of claim 1 wherein said masses are bi-dimensionallystabilized.
 3. The composition of claim 1 wherein said masses contain acrystallizable ingredient.
 4. The composition of claim 2 wherein saidamorphous masses are substantially rod shaped, having two dimensionslying in a cross-sectional plane of said rod and a third dimensionextending along the linear axis of said rod.
 5. The composition of claim1 wherein the cross section of each mass does not exceed about 50 μm. 6.The composition of claim 5 wherein the cross section does not exceedabout 10 μm.
 7. The composition of claim 1 wherein said activeingredient is selected from the group consisting of antitussives,antihistamines, decongestants, alkaloids, mineral supplements,laxatives, vitamins, antacids, ion exchange resins,anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics,analgesics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, anti-infectives,psycho-tropics, antimanics, stimulants, gastrointestinal agents,sedatives, antidiarrheal preparations, anti-anginal drugs,vasodialators, anti-hypertensive drugs, vasoconstrictors, migrainetreatments, antibiotics, tranquilizers, anti-psychotics, antitumordrugs, anticoagulants, antithrombotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypoglycemic agents, thyroid and antithyroid preparations, diuretics,antispasmodics, uterine relaxants, mineral and nutritional additives,antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics,cough suppressants, mucolytics, anti-uricemic drugs and mixturesthereof.
 8. A composition for making a quick dissolve comestible unithaving controlled release properties, said composition beingmicroparticulate and being made by mixing a controlled release systemand shearform masses using the following steps:i) initiatingcrystallization in the outer portions of amorphous saccharide-basedshearform masses, ii) before or after step i), combining a controlledrelease system with said masses to form micro-particulates, iii)compacting said micro-particulates to form a unit dosage, and iv)converting the remaining portions of said masses to a substantiallycompletely crystalline structure which is continuously bound andstabilized while incorporating said controlled release system in saidsaccharide-based crystalline structure.
 9. The composition of claim 8wherein said masses are bi-dimensionally monodispersed.
 10. Thecomposition of claim 8 wherein said masses contain a crystallizableadditive.
 11. The composition of claim 9 wherein said masses are rodshaped, having two dimensions lying in a cross-sectional plane of saidrod and a third dimension extending along the linear axis of said rod.12. The composition of claim 11 wherein the cross section does notexceed 50 μm.
 13. The composition of claim 12 wherein the cross sectiondoes not exceed 10 μm.
 14. The composition of claim 8 wherein saidcontrolled release system includes an active ingredient selected fromthe group consisting of antitussives, antihistamines, decongestants,alkaloids, mineral supplements, laxatives, vitamins, antacids, ionexchange resins, anti-cholesterolemics, anti-lipid agents,antiarrhythmics, antipyretics, analgesics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, anti-infectives, psycho-tropics, antimanics, stimulants,gastrointestinal agents, sedatives, antidiarrheal preparations,anti-anginal drugs, vasodilators, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, antitumor drugs, anticoagulants, antithrombotic drugs,hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromusculardrugs, hyper- and hypoglycemic agents, thyroid and anti-thyroidpreparations, diuretics, antispasmodics, uterine relaxants, mineral andnutritional additives, antiobesity drugs, anabolic drugs, erythropoieticdrugs, antiasthmatics, cough suppressants, mucolytics, anti-uricemicdrugs and mixtures thereof.
 15. An uncured composition for preparingcomestible units comprising compactible microparticulates consistingessentially of:(a) amorphous masses of sacchride-based shearform matrixparticles, (b) a controlled release delivery system, and (c) at leastone active ingredient, wherein the microparticulates can withstandcompaction force without experiencing an increase in density.